title: A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels.
abstract: BACKGROUND
  Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated.
  
  
  OBJECTIVE
  The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism.
  
  
  METHODS
  In 30 consecutive juvenile-onset AF patients (onset age <50 years), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations.
  
  
  RESULTS
  Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-IKs (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential.
  
  
  CONCLUSIONS
  A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University School of Medical and Dental Sciences, Niigata, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.affiliation: Department of Cardiovascular and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Pediatrics, Kinki University Faculty Medicine, Osaka, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Pediatrics, Kinki University Faculty Medicine, Osaka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism
chemical_list: D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D004247:DNA
keywords: AF; AP; Atrial fibrillation; CHO; Chinese hamster ovary; ECG; I(Ks); Ion channel; Juvenile-onset atrial fibrillation; KCNQ1; QTc; WT; action potential; atrial fibrillation; corrected QT interval; electrocardiogram; wild type